As the prevalence of type 2 diabetes continues to escalate, there is an urgent need for interventions that effectively prevent diabetic cardiovascular complications, which account for >50% of deaths in this population. Diabetes blocks the cardiac response to multiple pro-survival signaling pathways, rendering cardiomyocytes more susceptible to MI/R injury. The molecular mechanisms leading to universal impairment of cardio-protective signaling in the diabetic heart remain unclear. Cav-centered signaling complexes play essential roles in facilitating rapid, precise, and coordinated signal transduction broadly involved in cell protection and survival. However, whether and how Cav-signal complexes are altered and contribute to impairment of cardio-protective signaling remains unknown. Our preliminary experiments demonstrate that nitrative modification of Cav3 and resultant dissociation of Cav3 from its partner proteins occur during the early development phase of type 2 diabetes, blocking Cav3- dependent signaling. The current application will test a hypothesis that, in the diabetic heart, cardio-protective Cav3-signalsomes required by multiple cardio-protective interventions are impaired due to Cav3 nitrative modification at specific Tyr residue(s), resulting in the universal loss of pro-survival cardio-protective signaling cascades, contributing to increased diabetic patient mortality after MI. We will utilize advanced molecular/cellular technologies, and combine in vitro and in vivo approaches to identify the specific tyrosine residue(s) whose nitrative/oxidative modification results in disassembly of cardio-protective Cav3-signalsomes (Specific Aim 1), blocking their biological functions (Specific Aim 2), and reveal novel therapeutic strategies restoring cardio-protective signaling in the diabetic heart (Specific Aim 3), with the ultimate goal of reducing cardiovascular mortality in diabetic individuals. The novel data resulting from this application's proposed studies will define novel molecular mechanisms leading to the loss of cardio-protective response in diabetic heart, and potentially identify novel cardio-protective targets that may preserve/restore various cardio-protective signaling during early developmental diabetic stages.